1. Field of the Invention
The present invention relates generally to the fields of molecular genetics and pharmacology. More specifically, the present invention relates to novel triplex forming oligonucleotides for the treatment of human diseases.
2. Description of the Related Art
It is now generally accepted that a pathological situation is a result of deregulation or overexpression of certain cellular genes. During the last few years a great deal of insight has been gained into the mechanism by which cellular genes perform their function. It is this understanding which has led to the use of specific synthetic oligodeoxynucleotides to inactivate particular cellular genes in an attempt to correct certain abnormalities in the cell. Oligodeoxynucleotides that can interact with specific cellular mRNA and inhibit the activity or expression of its product has been in use for last several years. Oligodeoxynucleotides have also been described which bind specific proteins and inhibit their activity.
Recently, oligodeoxynucleotides have been described which inhibit cellular transcription by binding to duplex DNA to form a triple helix. Due to the possibility of long-term inhibition of the gene product, oligodeoxynucleotides that can bind duplex DNA have advantages over those that bind mRNA or proteins. These oligodeoxynucleotides are generally called triplex forming oligonucleotides (TFOs). By using DNA-specific TFOs, the inhibition of expression of several cellular genes has been demonstrated, including the oncogene, c-myc, the human immunodeficiency virus-1, the alpha chain of the interleukin 2 receptor, the epidermal growth factor receptor, the progesterone responsive gene and the mouse insulin receptor.
Tumor necrosis factor (TNF), a protein with a molecular mass of 17 kDa, was originally described as a product of activated macrophages and shown to display tumoricidal activity. Extensive research during the last few years has made it apparent that TNF is a highly pleiotropic cytokine and may play a role in tumorigenesis, septic shock, cachexia, inflammation, autoimmunity and other immunological and pathological reactions. Several different type of tumors have been described in which TNF acts as an autocrine growth factor, including different type of leukemias, ovarian tumors, renal cell carcinoma, breast adenocarcinoma and glioblastoma. These tumors express both TNF and its receptors and, furthermore, these tumors proliferate in response to TNF.
The prior art remains deficient in the absence of effective pharmacological therapies for a wide variety of neoplastic conditions. The present invention fulfills this longstanding need and desire in the art.